Seminar

Sickle-cell disease
David C Rees, Thomas N Williams, Mark T Gladwin
Lancet 2010; 376: 201831
Published Online
December 4, 2010
DOI:10.1016/S01406736(10)61029-X
Department of Paediatric
Haematology, Kings College
Hospital NHS Foundation
Trust, Kings College London,
London, UK (D C Rees FRCP);
Kenya Medical Research
Institute Centre for Geographic
Medicine Research-Coast, Kili,
Kenya (T N Williams PhD);
Nueld Department of Clinical
Medicine, University of Oxford,
Oxford, UK (T N Williams); and
Pulmonary, Allergy and Critical
Care Medicine and Vascular
Medicine Institute, University
of Pittsburgh, Pittsburgh, PA,
USA (Prof M T Gladwell MD)
Correspondence to:
Dr David C Rees, Department of
Paediatric Haematology,
Kings College Hospital NHS
Foundation Trust, Denmark Hill,
Kings College London, London
SE5 9RS, UK
david.rees@kcl.ac.uk

Sickle-cell disease is one of the most common severe monogenic disorders in the world. Haemoglobin polymerisation,
leading to erythrocyte rigidity and vaso-occlusion, is central to the pathophysiology of this disease, although the
importance of chronic anaemia, haemolysis, and vasculopathy has been established. Clinical management is basic
and few treatments have a robust evidence base. One of the main problems of sickle-cell disease in children is the
development of cerebrovascular disease and cognitive impairment, and the role of blood transfusion and
hydroxycarbamide for prevention of these complications is starting to be understood. Recurrent episodes of vasoocclusion and inammation result in progressive damage to most organs, including the brain, kidneys, lungs, bones,
and cardiovascular system, which becomes apparent with increasing age. Most people with sickle-cell disease live in
Africa, where little is known about this disease; however, we do know that the disorder follows a more severe clinical
course in Africa than for the rest of the world and that infectious diseases have a role in causing this increased
severity of sickle-cell disease. More work is needed to develop eective treatments that specically target
pathophysiological changes and clinical complications of sickle-cell disease.

Introduction

Pathophysiology

Sickle-cell disease is a multisystem disease, associated

with episodes of acute illness and progressive organ
damage, and is one of the most common severe
monogenic disorders worldwide.1 Herrick2 rst
described the characteristic sickle-shaped erythrocytes
in 1910 (gure 1), and understanding has gradually
increased since then (table 1). Pauling and colleagues5
identied electrophoretic abnormalities in sickle
haemoglobin (HbS) and coined the term molecular
disease in 1949. The haemoglobin biophysics and
genetics underlying the disease have been extensively
studied and have helped the understanding of other
molecular diseases. However, clinical management of
sickle-cell disease is still basic and, although some
evidence lends support to the use of blood transfusion
and hydroxycarbamide in some circumstances, no
drugs have been developed that specically target the
pathophysiology of this disease.

HbS is caused by a mutation in the -globin gene in which

the 17th nucleotide is changed from thymine to adenine
and the sixth aminoacid in the -globin chain becomes
valine instead of glutamic acid.21 This mutation produces a
hydrophobic motif in the deoxygenated HbS tetramer that
results in binding between 1 and 2 chains of two
haemoglobin molecules. This crystallisation produces a
polymer nucleus, which grows and lls the erythrocyte,
disrupting its architecture and exibility and promoting
cellular dehydration, with physical and oxidative cellular
stress.22 The rate and extent of HbS polymerisation is
proportional to the extent and duration of haemoglobin
deoxygenation, the intracellular HbS concentration (to
about the 34th power), and the presence of fetal
haemoglobin in the erythrocyte, which eectively reduces
the concentration of HbS.21,23 The main determinant of
disease severity is the rate and extent of HbS
polymerisation, which is exemplied by co-inheritance of
genetic factors that modulate the intracellular HbS or fetal
haemoglobin concentration, such as the protective eects
of co-inherited -thalassaemia or hereditary persistence of
fetal haemoglobin. Similarly, therapeutic inhibition of the

Classication
The term sickle-cell disease is used to refer to all the
dierent genotypes that cause the characteristic clinical
syndrome, whereas sickle-cell anaemia, the most
common form of sickle-cell disease, refers specically to
homozygosity for the S allele. In this Seminar, we mostly
discuss sickle-cell anaemia, because there is little
evidence for the management of other types of sickle-cell
disease. In populations of African ethnic origin, sicklecell anaemia typically accounts for 70% of cases of sicklecell disease, with most of the remainder having
haemoglobin SC disease (HbSC disease) owing to the coinheritance of the S and C alleles.13 The third major type
of sickle-cell disease occurs when S is inherited with a
-thalassaemia allele, causing HbS/-thalassaemia; this
is a variable disorder dependent on the type of the
-thalassaemia mutation.14 Apart from the many dierent
types of HbS/-thalassaemia, ten further genotypes that
cause sickle-cell disease have been described, although
most are rare (table 2).
2018

Search strategy and selection criteria

We searched Medline and EmBase from 1960 to May, 2010,
with the search term sickle in combination with the search
terms stroke, pain, infection, malaria, chest, kidney,
vaso-occlusion, haemolysis, nitric oxide, epidemiology,
screening, diagnosis, hydroxyurea, hydroxycarbamide,
blood transfusion, iron chelation, gene therapy,
transplantation, neurology, vasculopathy, pulmonary
hypertension, cardiac, and treatment. We mostly selected
publications from the past 5 years, but did not exclude
commonly referenced and important older publications.
Review articles and books are cited to provide readers with
more additional details and references. Our reference list was
modied on the basis of comments from peer reviewers.

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Seminar

cation transport channels prevents erythrocyte dehydration

and eectively reduces HbS concentration, and reduces
haemolysis; hydroxycarbamide increases fetal haemoglobin concentrations, reduces haemolysis, and prevents
acute vaso-occlusion.21 These manifestations are driven by
two major pathophysiological processes: vaso-occlusion
with ischaemia-reperfusion injury and haemolytic
anaemia (gure 2).
Acute vaso-occlusive pain is thought to be caused by
entrapment of erythrocytes and leucocytes in the
microcirculation, causing vascular obstruction and tissue
ischaemia. Although this process requires HbS
polymerisation, the event that triggers the vascular
obstruction by sickle erythrocytes is often inammatory.
As indicated in the microcirculation of transgenic mice
expressing HbS, cycles of experimental hypoxia or
treatment with inammatory drugs increase endothelialleucocyte-erythrocyte adhesive interactions in the
postcapillary venules and start vascular occlusion.2427 In
addition to inammatory triggers, precapillary obstruction
by rigid, deformed erythrocytes with high HbS polymer
content also contributes to microvascular vaso-occlusion.
Vascular occlusion is the result of a dynamic interaction
between erythrocytes and the vascular endothelium,
resulting in episodic microvascular occlusion and
ischaemia, followed by restoration of blood ow, which
further promotes tissue injury mediated by reperfusion.
These cycles of ischaemia and reperfusion cause oxidant
stress, with activation of vascular oxidases28 and
inammatory stress, increasing expression of endothelial
cell-adhesion molecules, increasing synthesis of
inammatory cytokines, and can cause leucocytosis.24,26,29
Bone marrow infarction leading to fat embolisation
might also contribute to vascular occlusion, particularly
in the lungs, where it causes acute chest syndrome.30
The second pathophysiological process in sickle-cell
disease is haemolytic anaemia, which is also driven by
HbS polymerisation. Haemolysis has long been known
to cause anaemia, fatigue, and cholelithiasis, but there is
now evidence that it contributes to the development of
progressive vasculopathy. As patients with sickle-cell
disease age, they are at risk of vasculopathy, characterised
by systemic and pulmonary hypertension, endothelial
dysfunction, and proliferative changes in the intima and
smooth muscle of blood vessels.3134 Data from
epidemiological studies suggest that several complications are associated with increased rates of haemolysis;
cholelithiasis, cutaneous leg ulceration, priapism, and
pulmonary hypertension are associated with low steadystate haemoglobin concentrations and an increased rate
of intravascular haemolysis.33,35 An association between
the development of pulmonary hypertension and the
intensity of haemolytic anaemia was noted in three
prospective screening studies of adults with sickle-cell
disease33,36,37 and in paediatric studies.38,39 Pulmonary
hypertension has also been reported in other forms of
chronic hereditary and acquired haemolytic anaemia.40
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S
NR

HJB
S

S
10 m

Figure 1: Peripheral blood smear of a patient with sickle-cell anaemia

This blood lm shows irreversibly sickled cells (S), a nucleated red blood cell
(NR), and a Howell-Jolly Body (HJB); these last two features are mainly
associated with hyposplenism (stained with May-Grunwald-Giemsa).
Discovery

Importance

1910

Sickled erythrocytes in Grenadan

dental student2

First description of disease

linked to abnormal
erythrocytes

1924

Haemolysis in sickle-cell disease3

Explanation for anaemia,

jaundice, and cholelithiasis

1924

Vaso-occlusion as cause of some

pathological features4

Explanation for ischaemic

tissue damage

1948

Abnormal electrophoretic mobility Identied pathophysiology

of sickle haemoglobin5
to have a molecular basis

1948

No symptoms in infants noted6

Benecial eects of high

concentrations of fetal
haemoglobin identied

1951

Characteristics of polymerisation
of deoxygenated HbS7

Primary molecular
mechanism identied

1980s Value of penicillin in young

children with sickle-cell anaemia8,9

Reduced mortality, role of

neonatal screening

1984

Bone marrow transplant in child

with sickle-cell anaemia and
leukaemia10

Identied potential cure

1995

Ecacy of hydroxycarbamide11

Only disease-modifying
drug identied

1998

Reduced stroke incidence in

children with abnormal
transcranial dopplers who were
given blood transfusion12

Primary stroke prevention

with fall in stroke
occurrence

Table 1: Important discoveries in the pathological and clinical features

of sickle-cell disease in chronological order

Therefore, patients with low haemoglobin concentrations

and high haemolytic rates seem to form a subphenotype
of patients who are more likely to develop vasculopathy
than are those with higher haemoglobin concentrations
who seem more prone to episodes of acute pain and,
possibly, acute chest syndrome.35 Although vaso-occlusion
is important in all patients, the role of haemolysis as a
pathophysiological mechanism in sickle-cell disease is
more controversial and is the focus of much research.
An important disease mechanism involves the release of
haemoglobin into the circulation during intravascular
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Seminar

Characteristics
Severe sickle-cell disease
HbS/S (6Glu>Val/6Glu>Val); sickle-cell anaemia

The most common form of sickle-cell disease

HbS/ thalassaemia

Most prevalent in the eastern Mediterranean region and India14

Severe HbS/ thalassaemia

Most prevalent in the eastern Mediterranean region and India; 15% HbA present14

HbS/OArab (6Glu>Val/121Glu>Lys)

Reported in north Africa, the Middle East, and the Balkans; relatively rare14

HbS/D Punjab (6Glu>Val/121Glu>Gln)

Predominant in northern India but occurs worldwide14

HbS/C Harlem (6Glu>Val/6Glu>Val/, 73Asp>Asn) Electrophoretically resembles HbSC, but clinically severe; double mutation in -globin gene; very rare15
HbC/S Antilles (6Glu>Lys/6Glu>Val, 23ValIle)

Double mutation in -globin gene results in severe sickle-cell disease when co-inherited with HbC;
very rare16

HbS/Quebec-CHORI (6Glu>Val/87Thr>Ile)

Two cases described; resembles sickle-cell trait with standard analytical techniques17

Moderate sickle-cell disease

HbS/C (6Glu>Val/6Glu>Lys)

2530% cases of sickle-cell disease in populations of African origin13

Moderate HbS/ thalassaemia

Most cases in the eastern Mediterranean region; 615% HbA present14

HbA/S Oman ( /6Glu>Val, 121Glu>Lys)

Dominant form of sickle-cell disease caused by double mutation in -globin gene; very rare18

Mild sickle-cell disease

Mild HbS/ thalassaemia

Mostly in populations of African origin; 1630% HbA present14

HbS/E (6Glu>Val/26Glu>Lys)

HbE predominates in southeast Asia and so HbSE uncommon, although frequency is increasing with
population migration19

HbA/Jamaica Plain (A/6Glu>Val, 68Leu/Phe)

Dominant form of sickle-cell disease; double mutation results in Hb with low oxygen anity; one
case described20

Very mild sickle-cell disease

HbS/HPFH

Group of disorders caused by large deletions of the -globin gene complex; typically 30% fetal
haemoglobin14

HbS/other Hb variants

HbS is co-inherited with many other Hb variants, and symptoms develop only in extreme hypoxia

Genotypes that have been reported to cause sickle-cell disease are listed. All include at least one copy of the S allele, in combination with one or more mutations in the
-globin gene. HbS=sickle haemoglobin. HbA=haemoglobin variant A. HbE=haemoglobin variant E. Hb=haemoglobin.

Table 2: Dierent types of sickle-cell disease

haemolysis. Free plasma haemoglobin generates reactive

oxygen species, such as the hydroxyl and superoxide
radical,41 which is a potent scavenger of nitric oxide.42 Nitric
oxide is normally produced by the endothelium and
regulates basal vasodilator tone, and inhibits platelet and
haemostatic activation and transcriptional expression of
nuclear factor B (NF B)-dependent adhesion molecules,
such as vascular cell-adhesion molecule-1, intercellular
cell-adhesion molecule-1, and the selectins.43,44 The release
of haemoglobin into the plasma during haemolysis
potently inhibits endothelial nitric oxide signalling, leading
to endothelial cell dysfunction and nitric oxide resistance.42,45
Haemolysis also releases erythrocyte arginase-1 into
plasma. Arginase metabolises plasma arginine into
ornithine, decreasing the required substrate for nitric oxide
synthesis and compounding the decreased bioavailability
of nitric oxide in patients with sickle-cell disease.46
Chronic depletion of nitric oxide and arginine might
also contribute to the hypercoagulable state in haemolytic
diseases. Studies have shown correlations between the
rate of haemolysis and levels of platelet activation and
procoagulant factors in the blood.47 Haemolysis is also
associated with the formation of erythrocyte microvesicles
containing phosphatidyl serine, which is an activator of
tissue factor; the numbers of microvesicles are increased
further by the functional asplenia present in patients
with sickle-cell disease48 (gure 2).
2020

Epidemiology
The global distribution of HbS is indicative of two
factors: selection for carriers through their survival
advantage in malaria-endemic regions and subsequent
migration. Four region-specic African haplotypes (the
Senegal, Benin, Bantu, and Cameroon haplotypes) and
one Asian haplotype (the Arab-India haplotype) have
been dened, providing support for the hypothesis that
the mutation causing HbS has occurred, and been
locally amplied, on at least two, and possibly several,
separate occasions.49 The evidence that malaria caused
this amplication, which was rst suggested more than
60 years ago,50 is now substantial. In addition to the
close geographic correlation between the frequency of
the HbS gene in populations and the historic incidence
of malaria49 (gure 3), evidence for the partial resistance
of carriers to all forms of Plasmodium falciparum malaria
has been reported in many populations.55,56 Although
the mechanism of this protection is yet to be fully
understood, it probably includes both innate and
immune-mediated mechanisms.57 The genetic defects
that commonly combine with HbS to result in sicklecell disease (HbC and -thalassaemia) have also occurred
through malaria selection,49,57 with the result that such
defects reach their highest frequencies in similar
populations.49 The prevalence of sickle-cell disease is
highest in sub-Saharan Africa. Although the scarcity of
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Seminar

Oxygenated erythrocyte containing HbS

Acute pain
Acute chest syndrome
Hyposplenism
Osteonecrosis
Nephropathy
Deoxygenated erythrocyte with polymerisation of HbS

Dehydrated, sickled erythrocyte

Infarction
Inammation
Increased expression of
VCAM-1 and other adhesion
molecules
Hypercoagulability
Occlusion of postcapillary venules (vaso-occlusion)

Reperfusion

Haemolysis

Free plasma haemoglobin,

inactivating NO and
generating reactive oxygen
species

Free radicals, causing

tissue damage

Pulmonary hypertension
Priapism
Leg ulcers
Cerebrovascular disease

NO
Functional NO deciency
Vasculopathy and endothelial dysfunction

Figure 2: Pathophysiology of sickle-cell disease

The roles of HbS polymerisation, hyperviscosity, vaso-occlusion, haemolysis, and endothelial dysfunction are shown. Deoxygenation causes HbS to polymerise, leading to sickled erythrocytes.
Vaso-occlusion results from the interaction of sickled erythrocytes with leucocytes and the vascular endothelium. Vaso-occlusion then leads to infarction, haemolysis, and inammation; inammation
enhances the expression of adhesion molecules, further increasing the tendency of sickled erythrocytes to adhere to the vascular endothelium and to worsen vaso-occlusion. Reperfusion of the
ischaemic tissue generates free radicals and oxidative damage. The damaged erythrocytes release free haemoglobin in to the plasma, which strongly bind to nitric oxide, causing functional nitric oxide
deciency and contributing to the development of vasculopathy. HbS=sickle haemoglobin. NO=nitric oxide. VCAM=vascular cell-adhesion molecule.

diagnostic facilities means that precise data are not

available, a recent estimate52 suggests that more than
230 000 aected children are born in this region every
year (074% of the births in sub-Saharan Africa), which
is about 80% of the global total. By comparison, the
yearly estimate of aected births in North America is
2600 and 1300 in Europe52 (gure 3).
Little is known about sickle-cell disease in Africa.58,59
Generally, diagnostic facilities are poor, routine
screening is absent, and, despite the fact that most
patients would survive if provided with a simple package
of inexpensive interventions,60 most die undiagnosed in
early childhood.
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Despite the high mortality associated with this disease

in Africa, the causes of death in aected children are
poorly documented. Although widely ascribed to two
diseasesbacteraemia and malaria14,58few substantial
data are available to lend support to either potential
cause. However, in a study undertaken in an African
population,61 both the range of organisms and the
frequency of bacteraemia caused by Streptococcus
pneumoniae and Haemophilus inuenzae in children with
sickle-cell disease were similar to those reported in
Jamaica and the USA.8,62 This nding suggests that, with
prophylaxis against both H inuenzae and S pneumoniae,
the occurrence of bacteraemia in children with sickle-cell
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Seminar

Eastern Mediterranean
region 6491

European
region 1292
American
region
9047

HbS allele frequency (%)

03
36
69
912
1215
>15

African
region
233 289

South-East
Asian region
26 037

Western Pacic
region 13

Figure 3: Global distributions of HbS and malaria

(A) This map shows the distribution of the HbS allele. It was constructed with digitised data derived from Cavalli-Sforza and colleagues.51 The gures indicate
estimates for the combined yearly total number of individuals aected by HbSS, HbSC, and HbS/-thalassaemia by WHO region (adapted from Modell and Darlison52).
(B) This map shows the global distribution of malaria (red) before intervention to control malaria (adapted from Lysenko and Semashko,53 and Hay and colleagues.54
HbS=sickle haemoglobin.

disease in Africa could be reduced by as much as 50%,

providing strong support for early diagnosis.
Although malaria is commonly thought of as a major
cause of death in African patients with sickle-cell disease,58
this opinion is supported by few data. Most published
reports have not had controls to enable comparisons of
risk with patients without disease, and several intervention
studies have not had the power to denitively assess the
risk of death in African patients with sickle-cell disease.63
In a study from Tanzania,64 the frequency of malarial
parasitaemia was lower in patients with sickle-cell
anaemia than in those with normal haemoglobin; of those
with sickle-cell anaemia in hospital, parasitaemia was a
risk factor for both severe anaemia (haemoglobin <50 g/L),
and death. Similarly, in a study in Kenya,65 mortality from
malaria was higher in children with sickle-cell anaemia
than in those with normal haemoglobin, although
2022

malarial prevalence in individuals with sickle-cell anaemia

was not increased.
With a historic background of low health spending and
high rates of overall child mortality, children born with
sickle-cell disease in Africa are given a low priority.
However, in view of the sustained declines in child
mortality that are being recorded throughout much of
Africa,66 a growing proportion of overall deaths in childhood
are now attributable to sickle-cell disease, and survivors
will place an increasing demand on health services. A
better understanding of the presenting features and natural
history of this disease in Africa will therefore be essential if
rational approaches to its diagnosis and management are
to be developed. There have been some encouraging signs
that attitudes to sickle-cell disease in Africa are changing;
the disease has now been recognised as a health-care
priority by both WHO and the United Nations. Early life
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Seminar

screening has been introduced in parts of several African

countries,67 and a network has been formed to support the
acquisition of evidence-based research (the Global Sickle
Cell Disease Network).

Phenotypic heterogeneity
The presentation and clinical course of sickle-cell disease
shows substantial variation. For example, in the
Cooperative Study of Sickle Cell Disease in the USA,68
39% of 3578 patients with sickle-cell anaemia had no
episodes of pain but 1% had more than six per year. Such
variability is characteristic of the disease and many of its
complications, including cerebrovascular disease, acute
chest syndrome, and premature death.
The two best established genetic modiers are
determinants of fetal haemoglobin concentrations and
co-inheritance of -thalassaemia. The maintenance of high
fetal haemoglobin concentrations beyond infancy has long
been recognised to ameliorate many aspects of sickle-cell
disease,6 including predicting increased life expectancy,30
and reducing the frequency of both acute pain68 and leg
ulcers.69 The fetal haemoglobin concentration in patients
with sickle-cell anaemia varies from 1% to 30%, and is
inherited as a quantitative genetic trait. Three major loci
have been identied, which account for up to 50% of this
variation in sickle-cell anaemia: the Xmn1 polymorphism
in the promoter region of the G globin genes,70 the HMIP
locus on chromosome 6q23.3,71 and BCL11A on
chromosome 2.72 Genetic variation at these three loci is
likely to account for some of the clinical diversity seen in
sickle-cell disease, as has already been reported for acute
pain,73 and could be targeted to help to improve prenatal
diagnosis and accuracy of neonatal prognostication.
-thalassaemia trait exists in up to 30% of patients of
African origin with sickle-cell disease,74 and is present in
more than 50% of patients with this disease in India75
and Saudi Arabia.76 -thalassaemia reduces the
concentration of haemoglobin in each erythrocyte,
decreasing the tendency of HbS to polymerise, which
results in increased haemoglobin concentrations and
decreased rates of haemolysis. The clinical eects of
-thalassaemia are variable but generally benecial for
patients, with reduced occurrence of stroke,77 gall stones,78
leg ulcers,74 and priapism,79 although pain frequency is
not reduced.68 Data from some studies indicate an
increased frequency of pain in patients with
-thalassaemia, possibly associated with the increased
haematocrit and blood viscosity.80
Several genetic association studies have been done to
try and link single nucleotide polymorphisms with
particular complications of sickle-cell disease. Some
associations are well described and make biological
sense, such as the link between UGT1A promoter
polymorphisms and gall stones.78 Most studies have
investigated large-vessel stroke, and two independent
studies have suggested an association with the tumour
necrosis factor promoter polymorphism at position
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308.81,82 Bayesian modelling with single nucleotide

polymorphisms from 12 genes can also predict risk of
stroke with 982% accuracy.83 However, most genetic
associations are tentative, and conrmatory studies
are needed.84
Environmental factors are poorly characterised, but
could give rise to a large amount of phenotypic variability,
as indicated by the much greater severity of sickle-cell
disease reported in Africa than that for other continents. In
tropical countries, increased episodes of acute pain in the
rainy season are reported.85 In temperate countries, the
eects of rain and cold might be important but are less
well documented, although windy weather has been linked
to an increased occurrence of pain.86 The eects of air
pollution are uncertain. Data from studies suggest that
high ozone concentrations might be linked to acute pain;
however, the importance of atmospheric concentrations of
nitric oxide and carbon monoxide is unknown.87,88

For more on the Global Sickle

Cell Disease Network see
http://globalscd.ning.com

General management
Diagnosis and screening
Diagnosis of sickle-cell disease is based on analysis of
haemoglobin. Typically, this analysis involves protein
electrophoresis or chromatography, which are cheap
techniques and widely available worldwide, although
haemoglobin mass spectrometry and DNA analysis are
being increasingly used because these techniques enable
high-throughput testing.89 Antenatal screening is
available to women in some countries to help to identify
couples who are at risk of having a baby with sickle-cell
disease, and to oer prenatal diagnosis.89 Universal
neonatal screening programmes are established in the
USA and England, with other programmes being
developed in Europe and Africa.67 Some of the
improvement in survival in sickle-cell disease over the
past few decades has been attributed to neonatal
screening, facilitating early access to prophylaxis with
penicillin, comprehensive care, and parental education
on the early detection of complications such as acute
splenic sequestration (panel 1).90

Hydroxycarbamide
Many cytotoxic drugs increase fetal haemoglobin
concentrations, which is potentially benecial in patients
with sickle-cell disease. Hydroxycarbamide was chosen for
studies of sickle-cell disease because of its oral ecacy and
low toxic eects,91 although other benecial eects have
subsequently emerged, including increasing haemoglobin
concentrations, decreasing platelet and white cell counts,
changing expression of adhesion molecules,92 and nitric
oxide generation.93 In a randomised controlled trial,11
hydroxycarbamide decreased the frequency of painful
episodes, acute chest syndrome, the need for blood
transfusion, and admission to hospital in patients with
sickle-cell anaemia. Many subsequent studies have shown
evidence of similar benet in both adults and children.94,95
Hydroxycarbamide is well tolerated, with dose-dependent
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Panel 1: Recommended outpatient management of

sickle-cell disease

Education for patients, parents, and carers

Monitoring of growth, development, and nutrition
Prescription of penicillin and monitoring of adherence
Administration of or organisation of vaccinations
specic for sickle-cell disease, including those against
pneumococcus and inuenza
Monitoring of school or work attendance
Recording of steady-state blood results and
physiological measurements (oxygen saturation,
blood pressure)
Monitoring of frequency of acute complications
Prescription and monitoring of hydroxycarbamide
as appropriate
Early detection and prevention of chronic complications,
including cerebrovascular disease (transcranial doppler
scanning), pulmonary hypertension, and renal disease
Provision of psychological support

Panel 2: Indications for blood transfusion in sickle-cell disease

Indications for acute transfusions
Acute exacerbation of anaemia
Typically caused by Parvovirus B19 infection, splenic or hepatic sequestration, or severe
vaso-occlusion; simple transfusion is necessary to increase haemoglobin concentrations to
8090 g/L
Acute chest syndrome
Early simple top-up transfusion is benecial, with exchange transfusion to reduce HbS to
less than 30% if deterioration of clinical condition occurs
Stroke or acute neurological decit
Urgent transfusion to increase haemoglobin concentrations to 100 g/L, and reduce HbS
to less than 30%, which typically requires exchange transfusion
Multiorgan failure
HbS to less than 30% with haemoglobin concentration of 100 g/L
Preoperative management
Target HbS of less than 30% before major surgery (cardiothoracic, neurosurgery), typically
requiring exchange transfusion; medium-risk or low-risk surgery might need simple
transfusion to increase haemoglobin concentration to 100 g/L
Indications for regular, long-term transfusions
Primary and secondary stroke prevention
Regular transfusions, either simple or exchange, to keep HbS less than 30%
Recurrent acute chest syndrome not helped by hydroxycarbamide
Regular transfusions, either simple or exchange, to keep HbS less than 30%
Progressive organ failure
Including hepatic, renal, cardiac, and pulmonary failure; little evidence-based practice and
transfusion strategies vary widely
Other indications
Recurrent splenic sequestration, complicated pregnancy
Controversial indications
Frequent acute pain, chronic pain, avascular joint necrosis, leg ulcers, priapism

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myelosuppression being the main short-term side-eect.

Concern has been raised about the possibility of
hydroxycarbamide predisposing towards malignant
disease, although there is little evidence to support this
notion.95 On the basis of studies in mice and several case
reports, there is also concern that hydroxycarbamide might
cause irreversible male subfertility, although this tenet
needs to be studied prospectively.96 Individuals who are
receiving hydroxycarbamide are generally advised to avoid
pregnancy and conception, although no evidence of
teratogenicity was reported in a study of 94 pregnancies in
which one member of the couple was taking the drug at
the time of conception.97
Hydroxycarbamide might have other benets,
including increasing life expectancy,98,99 protection
against cerebrovascular disease,100 and reduction of
hypoxaemia101 and proteinuria.102 On the basis of our
experience, 1030% patients in Europe and the USA
take hydroxycarbamide, although precise gures are not
available. Because of fears about toxic eects, use is
generally limited to patients after a severe clinical course,
although emerging data, particularly for prolonged
survival, suggest that this treatment is underused.103

Blood transfusion and iron chelation

Erythrocyte transfusion has an established role in the
management of both acute and chronic complications in
sickle-cell disease (panel 2). Transfusion corrects
anaemia, decreases the percentage of HbS, suppresses
HbS synthesis, and reduces haemolysis, all of which are
of potential benet. Erythrocytes can be given as a simple
additive transfusion or by exchange, in which blood is
also removed. Exchange transfusion is more likely to be
necessary if the intitial haemoglobin concentration is
high, or if there is a need for rapid decrease in HbS
percentage without increasing the haematocrit and blood
viscosity, typically in people with acute neurological
symptoms. Exchange transfusion is most eectively done
by use of automated apheresis machines, although use is
limited by diculties with venous access, especially in
children.104 Patients with sickle-cell disease are at risk of
alloimmunisation because of dierences between the
ethnic origin of blood donors and patients, and blood is
typically subject to an extended crossmatch for ABO, full
Rhesus (Cc/D/Ee), and Kell blood groups.105 In countries
where most of the blood donors are of European origin,
this procedure reduces alloimmunisation by 50% and is
recommended practice. Chronic blood transfusion is
inevitably associated with iron overload, although the
pattern of haemosiderosis seems dierent to that
described in thalassaemia; in particular, most iron
loading occurs in the liver, with little cardiac iron
deposition.106 Iron chelation is important in chronically
transfused patients with sickle-cell disease, mainly to
avoid liver damage; desferrioxamine can be given
parenterally, although the oral iron chelator deferasirox is
increasingly used with evidence of benet.107
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Seminar

Haemopoietic cell transplantation and stem-cell

gene transfer
Haemopoietic cell transplantation was rst used in sicklecell disease 25 years ago and is the only curative treatment.10
However, only a few hundred patients have received
transplantation worldwide, and this procedure is mostly
conned to children with HLA-compatible siblings, in
whom the procedure is safest. Most children with sicklecell disease have few overt complications, and haemopoietic
cell transplantation is only considered when serious
complications have occurred, most often in children with
cerebrovascular disease who are eectively dependent on
transfusions. Data from studies indicate an overall survival
of 9294%, event-free survival of 8286%, and a transplantrelated mortality of 7%.108 Balancing of the short-term risk
of death against the long-term complications of a chronic
disease is dicult. In a study,109 nine adults with sickle-cell
disease received transplantation with non-myeloablative
conditioning and long-term immunosuppression,
resulting in stable chimerism and resolution of symptoms;
further development of this approach is likely to increase
the number of transplants by both decreasing toxic eects
and increasing the numbers eligible for haemopoietic cell
transplantation. Further studies are now being planned
with haploidentical family donors using immunotolerance
induction strategies.
Gene therapy continues to oer promise. Lentiviralmediated gene transfer can correct haematological
defects and organ damage in mice with sickle-cell
disease,110 and a clinical trial has started in France.111
Future developments might include the use of induced
pluripotent stem cells as a source of haemopoietic
progenitors for gene therapy, and this approach recently
successfully corrected sickle-cell disease in mice.112

Management of specic complications

Acute pain
Acute pain is the most common reason for admission to
hospital for both adults and children, although it is more
common in teenagers and young adults than in young
children. Although acute vaso-occlusive pain is typically
self-limiting and does not result in permanent organ
damage, it is the most important complication from the
patients perspective, and increased frequency of pain is
associated with early death in patients with sickle-cell
anaemia who are older than 20 years.68 Frequent episodes
of acute pain are associated with sickle-cell anaemia
(compared with HbSC disease), high haematocrit, low
fetal haemoglobin concentrations,68 sibling history of
asthma,113 and nocturnal hypoxaemia.114 Opiate analgesia
is the mainstay in the management of severe pain, with
data from a randomised controlled trial indicating no
additional benet from ketoprofen.115 Management is
increasingly based on oral opiates, which seem to be
equivalent to parenteral opiates in children.116 A
condential enquiry into deaths of patients with sicklecell disease in the UK identied opiate-related oversedation
www.thelancet.com Vol 376 December 11, 2010

as a cause of death, emphasising the importance of careful

monitoring and the involvement of specialist pain
teams.117 Corticosteroids can also shorten episodes of
acute pain, although use of these drugs has mostly
stopped because of a high frequency of rebound pain and
hospital re-admission.118 In trials of poloxamer 188119 and
inhaled nitric oxide,120 marginal benets were reported
and a larger placebo-controlled trial of nitric oxide is being
analysed.121 Despite the importance of pain, no specic
treatments are available that can change the natural
history of an acute episode, and little research is being
done in this area.

Infection
Bacterial infections are a major cause of morbidity and
mortality in children with sickle-cell disease. The
increased susceptibility of aected children is likely to
result from several causes, including impaired splenic
function, defects in complement activation, micronutrient
deciencies, and tissue ischaemia.14 Several organisms,
including S pneumoniae, H inuenza, and non-typhi
Salmonella species, have been identied as important
causes of infection in developed countries,14 where
substantial improvements in prognosis have followed the
introduction of penicillin prophylaxis and immunisation
with conjugate vaccines directed against S pneumoniae
and H inuenzae type b.8,9,122 Similar organisms are
probably involved in most of the infections in patients in
sub-Saharan Africa,61 although data are less clear.58

Neurological complications
Sickle-cell anaemia is one of the most common causes
of stroke in children. Most cases are associated with
vasculopathy aecting the distal internal carotid and
middle cerebral arteries, although extracranial vasculopathy can also be present.123 Although the mechanisms
for stroke remain uncertain, contributory factors to this
vasculopathy include anaemia, leucocytois, hypoxaemia,
abnormal rheology causing endothelial damage,
functional nitric oxide deciency associated with
haemolysis,77,124 and impaired regulation of blood ow
causing hyperaemia.125,126 The vasculopathy seems to
start in infancy, with a rst-stroke incidence of 102 per
100 patient-years between the ages of 2 years and 5 years,
and 11% of patients with sickle-cell disease have had a
stroke by the age of 20 years.32 Vasculopathy can be
detected at an early stage by use of transcranial doppler
scanning. In the Stroke Prevention in Sickle Cell
Anemia (STOP) study,12 regular blood transfusion to
keep HbS below 30% reduced the risk of stroke by 90%
in patients with increased transcranial doppler velocities.
A programme of transcranial doppler screening has
been established in some countries, with evidence of a
decrease in stroke incidence.127 Studies are investigating the role of hydroxycarbamide in the prevention
of cerebrovascular disease.100 In the Stroke with
Transfusions Changing to Hydroxyurea (SWiTCH)
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Seminar

study, the ecacy of regular blood transfusions and iron

chelation was compared with hydroxyurea and
phlebotomy in children with sickle-cell disease and
stroke. However, the study was stopped prematurely
because of the high number of strokes in the hydroxyurea
group; no strokes occurred in 66 children receiving
blood transfusions, but seven strokes occurred in the
67 children taking hydroxyurea.128
Once a stroke has occurred, the risk of recurrence is
more than 60%, although this risk is substantially
reduced by starting a transfusion programme.129 Some
children have progressive vasculopathy, with a moyamoyalike syndrome and further strokes despite transfusion;
neurosurgical revascularisation might be helpful in these
circumstances.130
In studies in which MRI is used, up to 20% of children
with sickle-cell disease have silent brain infarcts,

typically involving watershed areas in the frontal

lobes.125 These pathological changes also seem to occur
in young children.131 Silent infarcts are linked to
neurocognitive problems, ts, and risk of further brain
infarction.125 The possibility of preventing progression
of these infarcts with blood transfusions is being
studied in a randomised controlled clinical trial.132
Cognitive impairment also occurs in the absence
of brain infarction, with a suggestion that this
neurological decit might be partly attributable to
anaemia and hypoxia.133
Intracranial bleeds occur in patients of all ages, but are
most common between the ages of 20 years and 30 years;
they are typically associated with either a moyamoya-like
syndrome or cerebral aneurysms. Treatment is
neurosurgical and the outcome is poor, with 26%
mortality at 2 weeks.32

Vaso-occlusion: increased HbS polymerisation

Regional
hypoxia

Erythrocyte
rigidity

Decreased
oxygen delivery

Desaturated
haemoglobin

41 integrin
VCAM-1

Shunting of
blood from veins
to arteries

Increased endothelial
VCAM-1 expression and adhesion

Fat embolism
Microvasculature occlusion
and bone marrow infarction

NO
Increased erythrocyte adhesion
in lung-pulmonary infarction

Inammation:
secretory
phospholipase A2

NO

Hypoventilation
and atelectasis
secondary to rib
and vertebral
infarction
Acute chest syndrome
Pulmonary infection*

Figure 4: Pathophysiology of acute chest syndrome

Infection or other inammatory stimuli cause pulmonary hypoxia and increased expression of endothelial adhesion molecules, including 41 and VCAM-1; this
precipitates HbS polymerisation and vaso-occlusion, causing further hypoxia and inammation and creating a constant cycle. Vaso-occlusion causes the release of
free plasma haemoglobin, which reduces NO availability, altering VCAM-1 expression. Vaso-occlusion and bone marrow infarction can cause fat embolism, further
damaging the pulmonary circulation. The stain shows oil-red O staining of pulmonary alveolar macrophages, showing the characteristic red lipid inclusions that are
diagnostic of fat embolism. Secretory phospholipase A2 concentrations, which increase in response to inammation and are known to be very high in acute chest
syndrome, further increase expression of adhesion molecules in the pulmonary vasculature, causing more vaso-occlusion. *29% Chlamydia pneumonia, 20%
Mycoplasma pneumonia, 2% Legionella pneumonia, 10% respiratory syncytial virus, 4% parvovirus, 3% rhinovirus, 2% parainuenza virus, 2% parainuenza A virus, 2%
cytomegalovirus, 1% Epstein-Barr virus, and 1% herpes simplex virus; Staphylococcus aureus was isolated in 5% of cases and Streptococcus pneumoniae in only 4% of
cases. Adapted from Murray and colleagues,137 with permission from Elsevier. VCAM-1=vascular cell-adhesion molecule-1. NO=nitric oxide.

2026

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Seminar

Acute chest syndrome

Acute chest syndrome is the second most common
cause of hospital admission in patients with sickle-cell
disease. It is a form of acute lung injury and is dened
as the development of a new alveolar pulmonary
inltrate involving at least one lung segment.134 This
syndrome is caused by a combination of infection,
fat embolism, and vaso-occlusion of the pulmonary vasculature. Severity varies, but 13% of patients
require mechanical ventilation and 3% die.135 Treatment
involves broad-spectrum antibiotics, bronchodilators,
and oxygen. If haemoglobin concentrations decrease
substantially or the patients clinical condition
deteriorates, blood transfusion is commonly given.
Support is increasing for the use of early top-up
transfusion, with exchange transfusion reserved for
severe cases.135 Dexamethasone can improve clinical
condition and reduce the need for blood transfusion in
children with acute chest syndrome, although use is
limited by the occurrence of rebound pain on stopping
Panel 3: Treatment options for some complications of
sickle-cell disease
Avascular necrosis of the femoral head
Possible benet from core decompression144 and autologous
bone marrow grafting145
Proliferative retinopathy
Role of laser photocoagulation uncertain;146 case reports of
benet from intravitreal bevacizumb147
Sickle hepatopathy
Emerging use of liver transplantation in severe liver disease148
Priapism
Adrenergic agonists form mainstay of preventive
treatment, with emerging use of phosphodiesterase-5
inhibitors and nasteride149

corticosteroids and by the concern about infection136

(gure 4).

Pulmonary hypertension
Pulmonary hypertension is an increasingly recognised
complication of sickle-cell disease in teenagers and adults.
In three prospective studies in adults,33,36,37 in which
echocardiography was used to measure tricuspid
regurgitant jet velocity, 20% of the participants had mild
elevation in estimated pulmonary artery pressures, dened
by a pulmonary artery systolic pressure greater than 35 mm
Hg (upper limit of normal is 32 mm Hg), and 9% had
moderate-to-severe pulmonary hypertension (>45 mm
Hg). Despite increases in pulmonary pressure that are
much lower than those observed in patients with idiopathic
or hereditable pulmonary hypertension, the prospective
risk of death associated with even mild pulmonary
hypertension is high in patients with sickle-cell disease.33,36,37
In a French study,138 despite the exclusion of patients with
low creatinine clearance, reduced lung capacity, and
liver diseaseall additional major risk factors for
the development of pulmonary hypertension6% of
385 patients had a mean pulmonary artery pressure of
greater than 25 mm Hg at right heart catheterisation.
Although this prevalence is lower than in studies using
echocardiography, the occurrence of pulmonary
hypertension is high compared with other diseases
associated with its development, and all deaths occurred in
those with pulmonary hypertension.138
We are not aware of any robust evidence about how best
to treat pulmonary hypertension in patients with sickle-cell
disease. Risk factors such as hypoxaemia, sleep apnoea,
pulmonary thromboembolic disease, restrictive lung
disease, left ventricular systolic and diastolic dysfunction,
severe anaemia, and iron overload need to be identied
and treated. Treatment options include hydroxycarbamide,
with regular blood transfusions if there is no response.134
In patients with severe pulmonary hypertension (tricuspid

Therapeutic approach

Specic examples

To reduce infective complications

Improve vaccination against Streptococcus pneumoniae

7-valent and 13-valent conjugated vaccines

To reduce tissue hypoxia

Treat sleep-disordered breathing, blood substitutes

Overnight oxygen, continuous positive airways

pressure, pegylated haemoglobin

To reduce erythrocyte dehydration

Inhibit Gardos channels and other cation channels

Magnesium, zinc, dipyridamole, senicapoc

To improve rheology

Block surfactant, endothelin receptors

Poloxamer-188, bosentan

To improve nitric oxide availability

Increase nitric oxide availability, release, and synthesis

Inhaled nitric oxide, arginine, nitrites, sildenal, statins

To reduce inammation

Treat with corticosteroids, secretory phospholipase A2

inhibitors

Dexamethasone, varespladib

To reduce erythrocyte adhesion

Treat with anticoagulants, reduce endothelial activation

To increase fetal haemoglobin production Treat with cytotoxic drugs, short-chain fatty acids,
immunomodulatory drugs

Heparin, sulfasalazine
Decitabine, butyrate, pomalidomide, lenalidomide

To reduce tissue damage

Treat with antioxidants

Glutamine, N-acetyl cysteine

Empirical use

Treat with phytomedicines

Nix-0699

Further information is reviewed by Hagar and Vichinsky.150

Table 3: Emerging therapeutic approaches for treatment of sickle-cell disease by mechanism

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2027

Seminar

regurgitant jet velocity 3 m/s), right heart catheterisation

is necessary to conrm diagnosis and to directly assess left
ventricular function. Endothelin receptor antagonists (eg,
bosentan and ambrisentan), prostaglandin-based therapy
(eg, epoprostenol, treprostinol, and iloprost), and the
phosphodiesterase-5 inhibitors (eg, sildenal) are all used
to treat idiopathic pulmonary hypertension and might be
of benet for patients with sickle-cell disease. Treatment
with oral sildenal improved exercise tolerance and
pulmonary hypertension in patients with sickle-cell
disease,139 although a multicentre, placebo-controlled trial
of sildenal for pulmonary hypertension in sickle-cell
disease was stopped early because of an unexpected
increase in hospital admissions for acute pain in the
treatment group.

Heart disease
Left-sided heart disease occurs in about 13% of adults with
sickle-cell disease and is mainly caused by diastolic
dysfunction; systolic dysfunction can also occur and
valvular disease is present in about 2% of patients.33 The
presence of diastolic dysfunction alone in patients with
sickle-cell disease is an independent risk factor for
mortality.140 Patients with both pulmonary vascular disease
and diastolic dysfunction are at a particularly high risk of
death (odds ratio for death 120, 95% CI 38381,
p<0001).140 Pulmonary pressures rise acutely during vasoocclusive pain and even more during acute chest
syndrome. In a study,141 13% of patients manifested right
heart failure with acute chest syndrome, and this subgroup
had the highest risk of mechanical ventilation and death.

Renal complications
Renal damage is almost inevitable in sickle-cell disease.
There is a strong tendency for HbS to polymerise in the
renal medulla, because of the low partial pressure of
oxygen, the low pH, and the high osmolality causing
erythrocyte dehydration. The consequent vaso-occlusion
causes renal infarction with papillary necrosis, and
medullary brosis with focal segmental glomerulosclerosis. Glomerular hyperltration and tubular
dysfunction also occur, and are possibly associated with
anaemia and increased sensitivity to prostaglandins.142
Renal dysfunction is apparent from an early age in
patients with sickle-cell anaemia, with glomerular
hyperltration apparent at 13 months.143 Microalbuminuria is common in childhood and up to 20% of
adults develop nephrotic-range protein loss, with more
than 35 g proteinuria in 24 h.142 30% of adults develop
chronic renal failure, which is a contributory factor in
many deaths.30 Other renal manifestations include
haematuria, renal medullary carcinoma, and nocturnal
enuresis.142 Treatment is beginning to focus on the early
use of hydroxycarbamide and angiotensin-converting
enzyme inhibitors in children with clinically signicant
albuminuria,102 although there is little supportive evidence
at present. In end-stage kidney failure, 10-year survival
2028

was 56% for patients after renal transplantation,

compared with 14% for patients on dialysis,142 suggesting
that transplantation is the treatment of choice.
Sickle-cell disease causes multisystem problems, and
panel 3 summarises new treatment approaches.

Future developments
Stem-cell transplantation and gene therapy seem likely to
become more widely applicable as new techniques
develop, with the use of induced pluripotent stem cells
oering the most promise.112 Data from genetic
association studies should help to identify more unlinked
and epigenetic factors to explain phenotypic diversity and
to enable better prognosis, which might lead to the
treatment of specic complications. Many drugs have
given in-vitro or early benet in sickle-cell disease without
becoming clinically useful, and table 3 lists some
promising pharmaceutical approaches in development.
Improved understanding of sickle-cell disease in Africa
would benet the largest number of patients, and could
facilitate improved management of patients worldwide,
including Europe and the USA.
Contributors
All authors contributed to the writing and editing of all sections of the
Seminar. MTG was mainly responsible for the sections on
pathophysiology and cardiopulmonary complications; TNW for the
sections on epidemiology, infection, and Africa; and DCR for the rest.
Conicts of interest
DCR has received consultancy fees from Sangart and speakers fees and
travel expenses from Novartis; he is chief investigator for the UK for a
clinical trial of conjugated pneumococcal vaccine sponsored by Wyeth,
and receives research funding from the UK Medical Research Council.
TNW is supported by the Wellcome Trust, UK (grant 076934) and the
European Virtual Institute for Malaria Research. MTG receives grant
support from the Institute for Transfusion Medicine, the Hemophilia
Center of Western Pennsylvania, PA, USA; and federal funding from the
National Heart, Lung and Blood Institute, National Institute of Diabetes
and Digestive and Kidney Diseases, and National Institute of Arthritis and
Musculoskeletal and Skin Diseases of the National Institutes of Health
(grants R01HL098032, RC1DK085852, and P30AR058910). He has
received money for grants or grants pending from the US Government.
His institution has received money grants or grants pending from the
National Institutes of Health, the US Government, and INO Therapeutics.
Acknowledgments
We thank Frederic Piel of the Malaria Atlas Project (University of Oxford,
Oxford, UK) for producing gure 3, and Vidhya Murthy and
Robin Ireland (Department of Haematological Medicine, Kings College
Hospital, London, UK) for gure 1.
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